tbuckley/cabot-search huggingface dataset:
Impact of oncology clinical pharmacist intervention on clinical trial enrollment in The U.S. Oncology Network’s MYLUNG Consortium.
Authors: Elizabeth Koselke, Shannon Hough, Josh Howell, Nicholas J. Robert, Marcus A. Neubauer, Susie A. Bullock, Jennifer M. Walberg, Melissa Rammage, James E. Butrynski, David Hakimian, Robert M. Jotte, Michael W. Meshad, Kashif Ali, David Michael Waterhouse, Robert L. Coleman, Makenzi Colleen Evangelist
Journal: Journal of Clinical Oncology (2022)

1503 Background: The Molecularly Informed Lung Cancer Treatment in a Community Cancer Network: A Pragmatic Consortium (MYLUNG) clinical trial platform aims to advance the use of precision medicine in non-small cell lung cancer patients through a series of prospective and iterative clinic trials. “Protocol 2” is evaluating the patient and tissue journey of newly diagnosed lung cancer patients presenting for care. Timely patient accrual to oncology clinical trials is a known practice challenge. The US Oncology Network recently implemented a clinical pharmacist (ClinReview) to provide remote clinical services to support Protocol 2 enrollment. Methods: An oncology-trained clinical pharmacist remotely reviewed chemotherapy regimen orders and a weekly custom recruitment report within six community network practices (n = 149 physicians). The ClinReview pharmacist identified, screened, and assisted with recruitment of eligible patients for enrollment in the MYLUNG study. Relevant and concise patient data were provided to the on-site research team to facilitate ease of enrollment. Enrollments and intervention data were tracked to monitor the impact of the pharmacist intervention. The primary outcome of monthly enrollment was evaluated using a paired t-test. Results: Over a 6-month period, the ClinReview pharmacist screened 367 potentially eligible patients, 325 patients were recommended for enrollment, and 103 patients (32%) were consented and enrolled. Enrollment due to this ClinReview intervention increased monthly and ranged from 5 in first month to 33 enrollments in month 6. Average monthly enrollment was significantly greater after ClinReview intervention (3.4 patients/month vs. 6.8 patients/month; p = 0.008). Of the 154 patients recommended for enrollment that were not enrolled, 104 (68%) exceeded their eligibility window allowed by the trial, 15 (10%) were deceased or enrolled into hospice care, 10 (6%) declined trial participation, and 25 (16%) transferred care or were treated at outside facilities. Conclusions: We demonstrate that incorporation of an oncology clinical pharmacist in clinical research teams significantly enhanced clinical trial enrollment. The remote pharmacist easily adapted into clinic workflows in community practices. Validation across a broader spectrum of differentially resourced oncology practices will be conducted as the MYLUNG clinical trials platform is executed. [Table: see text]
IMMU-16. Next-generation CAR T-cells targeting IL13RA2 and secreting IL-15 achieve durable tumour clearance in pre-clinical model of diffuse midline glioma
Authors: Alastair Hotblack, Patrycja Wawrzyniecka, Gordon Weng-Kit Cheng, Francesco Nannini, Martin Pule, Karin Straathof
Journal: Neuro-Oncology (2022)

Abstract T-cells engineered with a chimeric antigen receptor (CAR) to acquire tumour specificity provide a possible new treatment approach for childhood brain tumours. Durable clinical remissions have been achieved with CD19-directed CAR T-cells in refractory B-cell malignancies including control of leptomeningeal disease and parenchymal deposits. Early clinical data of CAR-T cells in adult glioblastoma and diffuse midline glioma (DMG) further support the rationale for development of CAR-T cell therapy for paediatric high-grade gliomas (pHGG) and other high-risk childhood brain tumours. IL13RA2 provides a suitable CAR target. It is expressed in the majority of pHGG including DMGs while expression is absent on normal (paediatric) brain tissue. Early results with CAR T-cell therapy for adult HGG has shown that IL13RA2 can be safely targeted, and potent anti-tumour activity is possible. However, responses are variable and ultimately transient. This is likely due to the immunosuppressive environment encountered by CAR T-cells at tumour sites which hampers persistent tumour-directed immunity. Here we develop a next generation CAR approach engineering T-cells with both a CAR and a cytokine signal which supports persistent anti-tumour immunity. We have generated novel IL13RA2-specific antibodies and used these to construct CARs. Using a functional screening approach assessing target-specific cytolytic function, T-cell proliferation and cytokine release, we selected the optimal IL13RA2-CAR design. Then, we generated a next generation CAR construct co-expressing inflammatory cytokine IL-15 with the IL13RA2-CAR. In a PDX model of DMG, T-cells transduced with IL13RA2-CARIL-15, in contrast to IL13RA2-CAR alone, induced long-term tumour clearance. Further in vitro testing of IL13RA2-CARIL-15 showed enhanced proliferation and resistance to immune-suppressive secreted factors such as TGF-β. In conclusion, co-expression of IL-15 with IL13RA2-CAR enhances CAR T-cell proliferation and in vivo persistence and achieves durable tumour clearance. IL13RA2-CARIL-15 is being translated into a phase I clinical trial for patients with DMG.
OTHR-46. Single institution experience using molecular analysis of pediatric CNS tumors
Authors: Anne Bendel, Mary Skrypek, Dinel Pond, Damon Olson, Kris Ann Schultz, Samuel Roiko
Journal: Neuro-Oncology (2022)

Abstract Molecular analysis of pediatric CNS tumors helps confirm the diagnosis, but can also guide treatment by identifying prognostic factors allowing for treatment stratification, and by unveiling active signaling pathways which can be targeted. This report is a retrospective review of the molecular analysis performed on all CNS tumors biopsied or resected at Children’s Minnesota over the last 3 years to evaluate our current practices. From 2019-2021, 118 patients with newly diagnosed CNS tumors underwent surgery followed by molecular assessment (14 IHC/FISH, 85 NGS, 7 methylation profiling) on 100% of medulloblastoma, other embryonal tumors, and schwannoma; 90% of ependymoma; 88% of HGG; 71% of LGG/glioneuronal/neuronal tumors; and 50% of meningioma and craniopharygioma. MAPK pathway alterations were seen in 84% of LGG/glioneuronal/neuronal tumors, with KIAA1540-BRAF fusion seen exclusively in pilocytic astrocytoma and BRAFV600E alterations seen in diffuse LGG (75%), PLNTY and PXA. Frequent alterations seen in HGG included H3F3A-K27M, H3F3A-G34, TP53, PDGFRA, ATRX, CDKN2A/B. Common gene alterations in medulloblastoma included monosomy 6 (100%) and alteration of CTNNB1 (50%) in WNT subgroup; PTCH1 (75%) in SHH subgroup; MYC/MYCN gain (60%) or amplification (60%) in Non-WNT/SHH subgroup. Alterations in FOXR2 in CNS neuroblastoma, SMARCB1 in ATRT and C19MC in ETMR confirmed these diagnoses. Supratentorial ependymoma showed ZFTQ-RELA fusion (100%) and infratentorial ependymoma showed chromosomal copy number changes including 1q gain (40%). Meningiomas showed deletion of NF2 and SMARCB1 and craniopharyngioma had alterations in CTNNB1. Molecular analysis confirmed the diagnosis in 23% of tumors, aided with targeted treatment in 20% of patients (82% of HGG, 9% of LGG, 13% of medulloblastomas) and allowed for risk-adapted treatment in 93% of medulloblastomas. These findings indicate that identification of pathogenic variants in CNS tumors aids in the diagnosis and treatment of pediatric CNS tumors and should be considered standard practice.
Thromboembolism (TE) and association with survival in patients (pts) with melanoma receiving chemo– or immunotherapy.
Authors: Tamara A. Sussman, Long Vu, Elizabeth Iannotti Buchbinder, Patrick Alexander Ott, Sarah C. Markt, Siran M. Koroukian, F. Stephen Hodi, Alok A. Khorana
Journal: Journal of Clinical Oncology (2022)

12082 Background: Emerging reports suggest high rates of venous thromboembolism (VTE) and arterial thromboembolism (ATE) with immune checkpoint inhibitors (ICI) in pts with melanoma, but it is unclear whether these are truly increased compared to older systemic therapy approaches. We assessed the incidence of TE in melanoma pts on ICI, cytokine therapy (CY), and chemotherapy (chemo), and evaluated its impact on survival. Methods: We conducted a cohort study using the SEER-Medicare database to evaluate rates of TE in pts with melanoma treated from 2008-2019 with ICI (ipilimumab, nivolumab, pembrolizumab), CY (IL2, IFN), and/or chemo (antineoplastic agents, BRAF/MEK inhibitors) within two years of treatment initiation. TE including VTE events of deep venous thrombosis, pulmonary embolism, and ATE of MI, ischemic stroke, and transient ischemic attack were identified by at least two outpatient claims or one inpatient claim. Overall survival (OS) from treatment start was analyzed by time-varying Cox analysis. Results: The cohort comprised 13,124 pts with median age 75 (24-101) years and 68% male. Of these, 14.8% received ICI, 48.9% chemo, 1.7% CY, 31.8% chemo+ICI, and 2.8% chemo+CY. At treatment start, comorbidities included 72% of pts with hypertension, 33% cerebrovascular disease, 17% atrial fibrillation, 7.3% history of VTE, and 13.0% history of ATE. Overall, 11.4% were on anticoagulation and 5.2% on antiplatelet agents. Incidence rates of ATE and VTE after treatment start are shown (Table). VTE was highest at 3 months after starting therapy with 19.6 events per 100 person-years in those receiving chemo+ICI, 17.1 events with chemo, 15.4 events with ICI, 10.1 events with chemo+CY, and 7.7 events with CY. In multivariable analysis, VTE and ATE were associated with worse OS compared to patients without (HR 2.77 [95%CI, 2.50-3.08], and HR 2.53 [95%CI, 2.23-2.86], respectively). Conclusions: Systemic therapy with ICI and chemo, especially when exposed to both sequentially or concurrently, demonstrates a high incidence of TE in pts with melanoma. TE is associated with substantial worsening of survival. TE rates are not substantially increased with ICI in comparison to chemo. Further studies are needed to identify benefit of thromboprophylaxis.[Table: see text]
Sustained castration to &lt; 20 ng/dl for relugolix vs. leuprolide in men with advanced prostate cancer: Results from the phase 3 HERO study
Authors: B. Tombal, N.D. Shore, D.J. George, M.S. Cookson, D.R. Saltzstein, B. Mehlhaff, R. Tutrone, J.L. Bailen, B. Brown, S. Lu, T. Schulmann, S. Hanson, F. Saad
Journal: European Urology (2022)
OTHR-28. Multi-institution analysis of tumor mutational burden and outcomes in pediatric CNS tumor patients
Authors: Rose Parisi, Roshal Patel, Gavrielle Rood, Acacia Bowden, George Turco, David Korones, Jeffrey Andolina, Melanie Comito, Matthew Barth, Lauren Weintraub
Journal: Neuro-Oncology (2022)

Abstract Pediatric CNS tumors are the leading cause of pediatric cancer mortality. Research addressing genomic biomarkers and clinical outcomes is needed to inform therapeutic decision making. Tumor mutational burden (TMB) has been correlated with decreased survival across cancer types. This study is the first to examine TMB and outcomes in pediatric CNS tumor patients across multiple academic medical centers. We conducted a retrospective analysis of 121 pediatric patients (61 female (50%)) with a median age of 9 diagnosed with a primary CNS tumor at Albany Medical Center, Roswell Park Comprehensive Cancer Center, Upstate University Hospital, or University of Rochester Medical Center from 2008 to 2021. Common tumor types included low-grade glioma (N=51), high-grade glioma (N=30), medulloblastoma (N=11), ependymoma (N=7), ganglioglioma (N=4), and 18 other CNS tumors. Seventy-one patients had driver-mutations, including TP53 inactivation (n=17), BRAF-KIAA1549 fusion (n=16), FGFR1 amplification (n=12), BRAF V600E mutation (n=12), NF1 loss (n=12), and H3F3A K28M mutation (n=6). TMB data was available for most patients (N=91), median TMB was 1 mutations/megabase (mut/Mb, range=0-132). There were 26 deaths observed; patients with high TMB (≥3 mut/Mb; N=35) as compared to patients with low TMB (&amp;lt;3 mut/Mb; N=56) were more likely to have a death event, 43% (N=15) vs 9% (N=5), respectively. High TMB tumors were more frequently high-grade (77%) than low-grade (41%). High TMB tumors were more frequently treated with systemic therapy (86%) compared to low TMB tumors (70%). Tumor progression was more common in high TMB (71%) than in low TMB tumors (54%). This multi-institutional analysis suggests that high TMB is correlated with higher rates of progression and death as compared to low TMB tumors. Knowledge of these findings is critical for identifying patients who may benefit from alternative treatments, such as immunotherapies.
HGG-27. Understanding the role of PLAG family transcription factors in cortex development and tumorigenesis
Authors: Jan Vaillant, Nina Hofmann, Michaela-Kristina Keck, David T W Jones, Lena M Kutscher, Stefan M Pfister
Journal: Neuro-Oncology (2022)

Abstract Gliomas are the most common type of central nervous system (CNS) tumors in children. Therapy and outcome often reflect the grade of the tumor, with high grade glioma (HGG) leading to a significantly worse survival prognosis than low grade glioma. However, HGG are highly diverse regarding their molecular entities and clinical associations. In some pediatric-type histone 3 K27M mutated HGG, the zinc-finger transcription factor PLAG1 was previously found to be overexpressed, which is also confirmed by patient data from the INFORM program. Further, in a novel type of embryonic CNS tumors without histone mutations, the PLAG1-related genes PLAGL1/PLAGL2 are amplified. However, the consequences of aberrant PLAG gene expression on CNS tumor formation during development are unknown. Especially the understanding of downstream signaling pathways that are commonly altered by this transcription factor family could provide necessary starting points for more specific therapy. We use transgenic mouse models with targeted PLAG1 overexpression in neural stem and progenitor cells to investigate the function of PLAG1 in cerebral cortex development and tumorigenesis. We found that PLAG1 overexpression together with heterozygous loss of p53 activity causes neurological defects and impaired cortex development. Next, to understand how PLAG gene overexpression affects neural specification, we will overexpress the PLAG genes in embryonic neural stem and progenitor cells using in utero electroporation. After FACS isolation of electroporated cells and single nucleus RNA sequencing, we will assess how the overexpression changes the transcriptional trajectories of neural development in mouse cortex stem and progenitor cells. We hypothesize that an early event leads to the constitutive upregulation of PLAG genes, which are usually tightly regulated during development, in patients with pediatric brain tumors harboring aberrant PLAG gene expression. Deciphering the transcriptional downstream pathways of this aberrant expression in neural stem and progenitor cells seems promising to find new potential therapeutic targets.
Recombinant Zoster Vaccine Uptake and Risk of Flares Among Older Adults With Immune‐Mediated Inflammatory Diseases in the US
Authors: Jessica Leung, Tara C. Anderson, Kathleen Dooling, Fenglong Xie, Jeffrey R. Curtis
Journal: Arthritis & Rheumatology (2022)

Objective Persons with immune‐mediated inflammatory diseases (IMIDs) are at an increased risk of herpes zoster (HZ). In 2018, the Centers for Disease Control and Prevention recommended a highly efficacious vaccine, recombinant zoster vaccine (RZV), for prevention of HZ in immunocompetent patients ≥50 years of age. This study was undertaken to estimate RZV vaccination among adults ages ≥50 years with IMIDs during 2018–2019 and to examine possible vaccine‐related flares following RZV. Methods We identified a cohort of IMID patients using medical claims data from the IBM MarketScan (ages 50–64 years) and Centers for Medicare and Medicaid Services Medicare (ages ≥65 years) databases. Presumed flares were defined as hospitalization/emergency department visit for their respective IMIDs, or steroid treatment with a short‐acting oral glucocorticoid or parenteral glucocorticoid injection. We conducted a self‐controlled case series (SCCS) analysis to examine a temporal association between RZV and flares. Results Among enrollees with IMIDs, 14.8% of 55,654 MarketScan enrollees and 43.2% of 160,545 Medicare enrollees received ≥1 dose of RZV in 2018–2019. Two‐dose series completion rates were 76.6% in MarketScan enrollees and 85.4% in Medicare enrollees. In the SCCS analysis, 10% and 13% developed flares in the control window, compared to 9% and 11–12% in the risk window following 1 or 2 doses of RZV among MarketScan and Medicare enrollees, respectively. We found no statistically significant increase in flares following RZV administration for any IMID in either age group following RZV dose 1 or dose 2. Conclusion We did not find an increase in presumed flares following RZV vaccination. Among adults ages ≥50 years with IMIDs, a substantial proportion received RZV compared to general zoster coverage estimates, and series completion rates were high.
Germline PTPN13 mutations in patients with bone marrow failure and acute lymphoblastic leukemia
Authors: Houtan Moshiri, David A. Cabrera Riofrío, Yeon Jung Lim, Supanun Lauhasurayotin, Michal Manisterski, Ronit Elhasid, Francisco A. Bonilla, Santhosh Dhanraj, Richard N. Armstrong, Hongbing Li, Stephen W. Scherer, Angel Hernández-Hernández, Yigal Dror
Journal: Leukemia (2022)
On-clamp versus off-clamp robotic partial nephrectomy for totally endophytic deep renal masses: Propensity score-matched comparison of perioperative, oncologic and functional outcomes of a multicenter analysis (ROSULA database)
Authors: G. Tuderti, R. Autorino, A. Minervini, J. Kaouk, C. Lau, S. Perdonà, F. Porpiglia, I. Derweesh, A. Saidian, M. Nguyen, U. Carbonara, K.H. Rha, R. Schiavina, R. Mastroianni, L. Misuraca, A. Mari, A. Brassetti, U. Anceschi, A. Bove, M. Ferriero, A. Mottrie, M. Gallucci, G. Simone
Journal: European Urology (2022)
Low infiltration of CD8+ FOXP3+ T cells associated with favorable clinical outcomes after first-line targeted therapy in EGFR exon 21 mutated lung adenocarcinoma patients.
Authors: Kejun Liu, Quanquan Tan, Kai-Cheng Peng, Shiyuan Chen, Junwei Su, Chanyuan Zhang, Yuqing Chen, Ligang Wu, Xue Zheng, Hongbo Zheng, Beibei Mao, Shihao Zhang, Jun Jia, Jin-Ji Yang
Journal: Journal of Clinical Oncology (2022)

e21107 Background: As the standard first-line treatment for NSCLC patients with EGFR-sensitive mutation, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) were proved to be highly effective and less toxic compared to traditional chemotherapeutic regimens. But little is known about the correlation between tumor-infiltrating immune cells in the tumor microenvironment and clinical outcomes. This study was designed to investigate the association between tumor-infiltrating immune cells and the clinical outcome after first-line targeted therapy in EGFR exon 21 mutated lung adenocarcinoma (LUAD) patients. Methods: A total of 26 advanced LUAD patients with EGFR exon 21 mutation who received first-generation EGFR-TKIs as initial therapy between January 2017 and October 2019 were included in this study. All the patients were treated at Affiliated Dongguan Hospital, Southern Medical University, China. Patients who progressed within 12 months after first-line EGFR-TKIs therapy were defined as experiencing early progression (EP), and patients who progressed after 12 months or without progression were defined as experiencing late progression (LP). We analyzed immune markers in biopsy from these patients before treatment with EGFR-TKIs and examined the infiltration of immune cells and expression of PD-L1 in immune cells using fluorescent multiplex immunohistochemistry (mIHC) stained with CD8/CD56/CD68/CD163/FOXP3/PD-L1 antibodies. Results: In this cohort, we observed that after first-line EGFR-TKIs therapy in EGFR exon 21 mutated LUAD patients, the density of CD8+ FOXP3+T cells infiltrated in tumor area of LP group was significantly lower than EP group (P = 0.038). However, the difference of the density of the other infiltrated immune cells including CD8+T cells, FOXP3+Treg cells, CD8+PD-L1+T cells, CD68+CD163+M2macrophages, etc., were not significant between LP group and EP group (P &gt; 0.05). The “optimal” cutoff value for CD8+ FOXP3+T cells infiltrated in tumor area was 5.45 (n/mm2) using the survminer package in R software according to PFS. Kaplan-Meier analysis suggested that the density of CD8+ FOXP3+T tell infiltrated in tumor area contributed to risk factor for PFS (HR = 5.56, P = 0.00054). Taking 5.45 (n/mm2) as the cutoff value, the percent of LP patients in low density of CD8+ FOXP3+T cells infiltrated in tumor area group was close to being statistically significant higher than high density of CD8+ FOXP3+T cells group (47% vs. 0%. P = 0.058). Conclusions: This study indicated that the low density of CD8+FOXP3+ T cells infiltrated in tumor area was associated with favorable clinical outcome in EGFR exon 21 mutated LUAD patients treated with first-generation EGFR-TKIs at first-line.
Clinical and prognostic features of <i>BRAF</i> V600E-mutant resectable colorectal cancer: A single-center retrospective analysis of Chinese patients.
Authors: Mengling Liu, Xiaojing Xu, Yiyi Yu, Tianshu Liu
Journal: Journal of Clinical Oncology (2022)

e15505 Background: Molecular subtyping provides a fundamental basis for the selection of strategies for colorectal cancer treatment. Unresectable metastatic colorectal cancer (CRC) with BRAF V600E mutation have received great attentions due to the poor prognosis. Nevertheless, clinical characteristics and prognosis of Chinese patients with BRAF V600E-mutant (BM) resectable CRC remain poorly reported. Methods: Patients with BM resectable CRC were included according to the following criteria: 1) Diagnosed with colorectal adenocarcinoma at Zhongshan Hospital Fudan University from June 2015 to December 2018. 2) Underwent surgery for the primary tumor of CRC without any anti-tumor treatment before surgery. 3) With BRAF V600E mutation confirmed by the genetic test of the primary tumor tissue. 4) No other primary malignant tumors or inherited tumor history. 5) Written informed consent was obtained. Clinical information was collected by consulting electronic medical records with the approval of the Ethics Committee of Zhongshan Hospital Fudan University (Approval code: B2021-739). KRAS exon2 mutant (KM) and KRAS/BRAF wildtype (WT) patients were selected in a 1:1 ratio by matching gender, age, location and the year of surgery with the BM group. Overall survival was defined as the time from surgery to death for any reason or last follow-up (September, 2021). Categorical data were assessed by chi-square test. Survival analysis was performed using Kaplan-Meier survival curve with log-rank test, univariate and multivariate Cox regression analyses. Results: A total of 214 patients with BM resectable CRC met the inclusion criteria. Among them, 111 (51.9%) patients were females and 103 (48.1%) were males, 114 (53.3%) patients were younger than age 65 years while 100 (46.7%) were &gt; = 65 years old, 108 (50.5%) patients’ primary lesions sited on the left side and 106 (49.5%) on the right side. Numbers of patients with resectable metastasis and with mismatch-repair- deficient (dMMR) were both 48 (22.4%). 171 KM patients and 165 WT patients were matched with BM patients and the three groups were balanced in gender, age, and location by matching. The BM group had the worst overall survival ( P &lt; 0.001) with significant higher proportions of stage IIĨIV ( P = 0.002) and dMMR patients ( P &lt; 0.001). Survival analysis in subgroups suggested that the inferior prognosis of the BM group was more pronounced in patients with pMMR or Stage IV CRC. Conclusions: BRAF V600E-mutant resectable CRC presented a higher incidence of dMMR but a worse prognosis than KRAS exon2 mutant or KRAS/BRAF wildtype patients.